Molecular Human Reproduction, Vol. 6, No. 11, 1033-1040,
November 2000
© 2000 European Society of Human Reproduction and Embryology
Pregnancy |
Prostaglandin E2-dependent production of latent matrix metalloproteinase-9 in cultures of human fetal membranes
Preterm Birth Research Group, Department of Obstetrics and Gynaecology, University of Leicester, PO Box 65, Leicester LE2 7LX, UK
Abstract
Studies in our laboratory have shown that structural changes in cervical biopsied fetal membranes, prior to labour, coincide with differences in the expression of the gelatinase enzyme, latent matrix metalloproteinase-9 (MMP-9). Concurrently, in vivo, there is an increase in the expression of prostaglandins, notably prostaglandin E2 (PGE2), which has been shown to regulate the expression of MMPs in other systems. The aim of this study was to test the hypothesis (using an in-vitro culture model) that endogenously produced PGE2 has a role in the elevation of MMP-9 described in vivo. Non-infected fetal membranes sampled from women undergoing elective Caesarean section were stimulated with 10% (v/v) fetal bovine serum (FBS), a known inducer of prostaglandins. This activation resulted in a time-dependent increase in the secretion of PGE2 into the media, as determined by enzyme-linked immunosorbent assay (day 1: 19 ± 9 pg/ml/24 h to 358 ± 54 pg/ml/24 h by day 4). A similar pattern of secretion of latent MMP-9 was observed in parallel with the increase in PGE2 in the same culture media (day 1: 1.63 ± 0.17 ng/ml/24 h to 4.2 ± 1.4 ng/ml/24 h by day 4). When both molecules were compared, a significant (P < 0.01) positive correlation (r = 0.623) was observed. Secretion of the tissue inhibitor of MMPs-9 (TIMP-1) was not significantly different between untreated (3.07 ± 0.266 µg/ml/24 h) and FBS-treated (3.85 ± 0.24 µg/ml/24 h) cultures during the first 4 days in culture. Prostaglandin synthesis inhibition studies using indomethacin (100 µmol/l) resulted in a 70–80% reduction in the activated secretion of latent MMP-9. Direct PGE2 stimulation of cultures resulted in the bell shaped dose–response curve with concentrations of 1–100 nmol/l (which are within the range secreted in culture in response to FBS), stimulating significant latent MMP-9 secretion. These results suggest a link between endogenous PGE2 and latent MMP-9 production in human fetal membranes, raising the possibility that PGE2 has a role in the mechanism of fetal membrane structural changes and, hence, in parturition-associated membrane rupture.
human fetal membranes/indomethacin/MMP/parturition/prostaglandin E2
Introduction
Recent work has focused on fetal membrane remodelling, and the role of the degradative enzymes, the matrix metalloproteinases (MMP), in membrane rupture at term and preterm birth (Bryant-Greenwood, 1998
; Parry and Strauss, 1998). MMPs are a family of proteolytic enzymes responsible for the degradation of most of the components of the extracellular matrix (Nagase and Woessner, 1999). Their ultimate activity depends on the balance between activation and inhibition, particularly through binding with the tissue inhibitors of MMPs (TIMPs).
Studies in our laboratory have shown that structural changes seen within biopsies of fetal membranes overlying the cervix (McLaren et al., 1999) prior to labour, correspond with increases in the concentrations of the gelatinase enzyme, latent MMP-9, in the same area (McLaren et al., 2000). In addition, structural changes similar to, but more extensive than, those seen prior to labour have also been seen along the rupture line following labour and delivery (Malak and Bell, 1994). Although a general increase in both latent and active forms of MMP-9 have been reported during and after labour/delivery (Vadillo-Ortega et al., 1995), it was also noted that a further increase is seen along the rupture site.
The factor(s) responsible for the regional increase in the latent MMP-9 expression prior to labour are unclear. Prostaglandins, especially prostaglandin E2 (PGE2), have been suggested since increases are seen in amniotic fluid (Dray and Frydman, 1976; Romero et al., 1996) and within the forewaters in the lower uterine segment (Casey and MacDonald, 1993), prior to labour. Decreased prostaglandin metabolism has also been observed within the fetal membranes overlying the lower uterine segment during this period (Van Meir et al, 1997) and could result in the elevation of prostaglandins within the same region as that demonstrating elevations in latent MMP-9 (Van Meir et al., 1997). In addition, previous fetal membrane culture experiments have shown a direct stimulatory effect of PGE2 on unspecified collagenase activity (Koay et al., 1986)
In order to investigate the possible relationship between PGE2 and the gelatinases we used a short-term primary culture model employing whole fetal membranes to provide a system representative of the normal in-vivo environment. Membranes were cultured in media containing fetal bovine serum (FBS) which has been shown to induce prostaglandins, including PGE2, in amnion, chorion and decidual cells, with maintained cell viability (Edwin and Mitchell, 1992).
The aim of this study was to investigate the possible regulatory relationship between PGE2 and the gelatinases in human fetal membranes. Such a mechanism would provide a potential link between prelabour changes in the local endocrine milieu and the extracellular matrix remodelling in fetal membranes, which occur prior to membrane rupture.
Materials and methods
Patient details
Fetal membranes, unaffected by labour or delivery were obtained from women (n = 10) undergoing elective Caesarean section at 38–39 weeks gestation for repeat Caesarean section, breech or cephalopelvic disproportion. Fetal membrane tissue samples were obtained within 5–10 min post-operation, and the culture set up time was 30–40 min. Infected membranes (n = 3) were excluded following retrospective identification of polymorphonuclear infiltration or detection of interleukin (IL)-1ß (see below). In total, membranes from seven patients were cultured to completion in the absence of infection.
Culture conditions
The tissue culture system employed has been used previously (McLaren et al., 1998). Tissue samples were taken from the mid-zone region of the fetal membrane which exhibits a stable structural morphology (Malak and Bell, 1994; McLaren et al., 1999) and prostaglandin synthesis (Sawdy et al., 1999). Stable morphology was confirmed following examination of pre-culture fetal membrane sections stained with haematoxylin and eosin (H&E). An 8mm biopsy of the whole thickness of the fetal membrane was taken and rinsed in unsupplemented Dulbecco's minimal essential medium (DMEM) containing glutamax-1 (Gibco, Paisley, Scotland, UK). These biopsies were then placed with the amnion uppermost into one well of a 24-well Falcon plate, containing 1 ml of unsupplemented DMEM and incubated at 37°C for up to 6 days in an atmosphere of 95% air:5% CO2. Experiments were performed in duplicate and, unless otherwise stated, the culture medium was sampled and changed every 24 h and stored at –80°C prior to assay. No antibiotics were used and any visible signs of infection resulted in the discarding of the entire culture.
Infected membranes
The presence of infected membranes in the absence of visible signs of infection was assessed by the measurement of the infection-associated cytokine, IL-1ß (McDuffie et al., 1992). Previous work has demonstrated the association between IL-1ß production and fetal membrane infection (Menon et al., 1995). Membranes expressing significant amounts of IL-1ß, by enzyme-linked immunosorbent assay (ELISA), were discarded. Positive controls consisted of membranes stimulated with lipopolysaccaride (LPS; 10 ng/ml).
Culture cell viability
The viability of the fetal membrane biopsies was determined by the measurement of lactate dehydrogenase (LDH) leakage into the medium, over the 6 days in culture. This is a well-characterized method for the measurement of cell/tissue viability (Schraufstatter et al., 1988). A 500 µl sample of media was taken every 24 h, and LDH activity determined after adding the reduced form of nicotinamide adenine dinucleotide (NADH; 0.2 mmol/l final concentration) and pyruvic acid (1.36 mmol/l final concentration) and measuring the change in absorbance at 340 nm due to the oxidation of NADH. This represented the activity due to leakage from non-viable cells. Total LDH activity was measured following the addition of Triton X-100 (10% v/v), which causes cell lysis, to the remaining media and tissue biopsy.
Serum treatment
The effect of FBS (Gibco) on the secretion of PGE2, and gelatinase expression from cultured fetal membranes was determined. Fetal membranes (n = 7) were cultured as described above and were incubated with or without 10% FBS (v/v). Conditioned culture media was sampled every 24 h for up to 6 days and stored at –80°C before being assayed.
Inhibition of prostaglandin synthesis
The effect of inhibiting prostaglandin synthesis on latent MMP-9 secretion was also assessed. A key enzyme in prostaglandin synthesis is cyclo-oxygenase (COX) which exists in two forms, COX-1, which is generally considered to be constitutively expressed, and inducible COX-2 (Rustgi, 1998). Both these forms are localized in human fetal membranes mainly within the amnion and chorion laeve (Mijovic et al., 1998). Fetal membranes (n = 3) were cultured for up to 3 days with 10% FBS in the presence or absence of the general COX inhibitor indomethacin (100 µmol/l). This enzyme media was collected daily and replaced with fresh media.
Incubation of fetal membranes with PGE2
Fetal membranes (n = 3) in the absence of FBS were initially incubated for 24 h with indomethacin (100 µmol/l). After this period, the cultures were pulsed for 24 h with PGE2 dissolved in absolute ethanol (1 pg/ml–10 µg/ml). Controls consisted of non-treated cultures in the presence of inhibitor and ethanol vehicle (2 µl/ml).
Gelatin zymography
The identity and semi-quantification of the gelatinases secreted into the culture media was assessed by gelatin zymography. This procedure results in the artificial activation of both the inactive latent and the active forms of MMP, which are identified as separate bands on the gel. MMP-9 (latent 92 kDa, active 83 kDa) and MMP-2 (latent 72 kDa, active 66 kDa) activity was determined by gelatin zymography on 10% sodium dodecyl sulphate (SDS) gels incorporating 1 mg/ml gelatin (Novex, San Diego, CA, USA). Culture media samples were loaded, 15 µl/well and then subjected to electrophoresis under non-reducing conditions for 4–5 h at 75 mV. Controls of non-treated and 10% FBS (identical batch)-supplemented media were included. Prestained molecular weight markers were included together with the conditioned media from the HT1080 fibrosarcoma cell line, as a positive control for the latent MMP forms. Gels were scanned and images inverted for analysis, visible bands were semi-quantified by densitometry using Scion Image Software.
Enzyme-linked immunosorbant assay
Commercially-available ELISA kits for both latent MMP-9, IL-1ß, TIMP-1 (Amersham, Little Chalfont, UK), and PGE2 (R&D, Abingdon, UK) were used. The ELISA kit for latent MMP-9 provided a linear standard curve between the range of 1–32 ng/ml with a sensitivity 0.6 ng/ml. The PGE2 ELISA kit had a range of 20– 640 pg/ml with a sensitivity of 16 pg/ml. The TIMP-1 ELISA kit provided a linear standard curve between the range of 5–40 ng/ml with a sensitivity of 1.25 ng/ml. Values were expressed as compound released/ml/24 h. Controls of non-treated and 10% FBS (identical batch)-supplemented media were included, and these values were subtracted from the sample values.
Statistical analysis
Duplicate values for each time point in each experiment were averaged before statistical analysis. The data was normally distributed, and one-way analysis of variance (ANOVA) was undertaken for comparisons between treatments and between time points. P < 0.05 was considered to be statistically significant.
Results
Viability
LDH secretion from fetal membranes cultured in DMEM in the presence or absence of FBS (10% v/v) demonstrated their cell viability, in the region of 77–89% throughout the culture period (Figure 1). No significant differences were apparent within or between the two groups. Initial light microscopy was undertaken on cross-sectional H&E samples, and although no obvious histological damage was evident throughout the time in culture (with or without FBS stimulation), changes in the structure were apparent by day 6. These included swelling of the spongy layer and epithelial cell creep from the amniotic epithelium (data not shown).
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Infection of cultures
Fetal membranes were cultured in the absence of antibiotics, which allowed for the rapid detection of occult membrane infections or infections caused by laboratory handling. To assess whether the absence of visual infection truly indicates the absence of infection per se, culture wells without the presence of visually-infected culture wells were measured for the secretion of the infection-associated IL-1ß (McDuffie et al., 1992
). The results showed (Figure 2) that culture wells without the visual evidence of infection produced very low amounts of IL-1ß. However, visually infected membrane cultured wells showed significantly elevated amounts of IL-1ß, as did those artificially activated with the bacterial component lipopolysaccaride (LPS, 10 ng/ml). Infected membrane culture wells exhibited a similar rate of IL-1ß secretion to that seen following activation with LPS (Figure 2). Three culture experiments were discarded because of visually-detected infection.
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FBS stimulation of PGE2
Fetal membranes cultured in either the presence or absence of FBS (10% v/v) secreted PGE2 throughout the entire culture period (Figure 3
). A time-dependent significant (P < 0.01) increase in PGE2 secretion was apparent from day 1 (19 ± 9 pg/ml/24 h) to day 4 (358 ± 54 pg/ml/24 h) in FBS-treated (10% v/v) cultures. After this, the concentration of PGE2 fell significantly. No time-dependent secretion was evident in the non-treated cultures. A comparison between treated and non-treated cultures showed a significant increase (P < 0.01) in PGE2 secretion by day 2 with FBS treatment, and this was maintained for the remainder of the culture period (Figure 3).
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Identification of gelatinases
FBS treated or non-treated fetal membrane culture media were also assessed for the presence of gelatinases (MMP-2 and MMP-9). Gelatin zymography revealed that conditioned culture media from both treated and non-treated cultures predominately contained latent MMP-2 (72 kDa) and latent MMP-9 (92 kDa). No significant active-MMP-2 or MMP-9 bands were evident, irrespective of treatment (data not shown).
FBS stimulation of latent MMP-9
Initial gelatin zymography experiments showed increases in the latent MMP-9 band intensity following treatment with FBS (Figure 4a). These observations were subsequently quantified by ELISA. FBS treatment resulted in a significant time-dependent increase in the secretion of latent MMP-9 from day 1 (1.63 ± 0.17 ng/ml/24 h) up to day 4 (4.2 ± 1.4 ng/ml/24 h), after which the concentration fell significantly (Figure 4b). When individual treated and non-treated time points were compared, FBS (10% v/v)-treated cultures showed a significantly elevated secretion of latent MMP-9 for all time points from day 2 onwards.
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FBS stimulation and latent MMP-2
Initial semi-quantification of latent MMP-2 expression in gelatin zymography using densitometry indicated consistent expression throughout the 6 days of culture and this was unaffected by treatment with FBS (10% v/v; data not shown). No obvious difference in the amount of latent MMP-2 was evident between treated and untreated samples, for any time point. Therefore, further quantification of latent MMP-2 was not undertaken.
FBS stimulation and TIMP-1
TIMP-1 was determined in conditioned culture media, from both treated and untreated cultures, during the first 4 days of culture, the period during which the increases in latent MMP-9 and PGE2 were observed. There was no significant difference between untreated (3.07 ± 0.266 ± µg/ml/24 h) and FBS-treated (3.85 ± 0.24 µg/ml/24 h) cultures during the first 4 days in culture.
PGE2 and latent MMP-9 correlation
Since PGE2 and latent MMP-9 expression was analysed in the same culture supernatant, the relationship between their concentrations throughout the culture period was examined. Linear regression analysis demonstrated a significant (P < 0.01) positive correlation (r = 0.623) between PGE2 and latent MMP-9 secretion (Figure 5).
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Inhibition of FBS-stimulated prostaglandin and latent MMP-9 production by indomethacin
We then assessed the effect of direct inhibition of endogenous prostaglandin on the production of latent MMP-9 using the non-specific COX inhibitor, indomethacin, on FBS-treated cultures. Preliminary results (data not shown) showed that a concentration of 100 µmol/l was sufficient to completely inhibit all endogenous production of PGE2 within 24h, and that this concentration had negligible adverse effects on tissue viability as assessed by LDH leakage. Tissue was cultured for 4 days, since our earlier results showed a reduced responsiveness for FBS (10% v/v) stimulation after this time (Figures 3 and 4
). When analysed for latent MMP-9 production, it was found that the COX inhibitor had significantly reduced (70–80%; P < 0.01) the FBS-mediated production of latent MMP-9 throughout the culture period (Figure 6).
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PGE2 stimulation of latent MMP-9
The previous results suggest a link between prostaglandins and latent MMP-9 production in the fetal membrane. The ability of the membranes to produce latent MMP-9 following direct stimulation with prostaglandins was, therefore, examined. Endogenous prostaglandin production was inhibited by indomethacin (100 µmol/l) for 24 h and then pulsed for a further 24 h with PGE2 (1 pg/ml–10 µg/ml) in the absence of FBS. PGE2 stimulation resulted in a bell-shaped dose–response curve, with lower concentrations (<1 nmol/l) having a negligible inducible effect compared with the control, but concentrations of 1–100 nmol/l induced a significant elevation in the production of latent MMP-9 reaching values comparable with those seen following FBS stimulation (Figure 7
). Values of >100 nmol/l resulted in decreased latent MMP-9 production compared with the control.
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Discussion
The results of this study provide evidence of an association between serum-stimulated PGE2 and latent MMP-9 production in human fetal membrane cultures. Using our culture system we were able to demonstrate that the FBS-stimulated increases in PGE2 paralleled changes in the secretion of latent MMP-9, and that these increases were significantly reduced following inhibition of prostaglandin synthesis with the COX inhibitor, indomethacin. Linear regression analysis also demonstrated a significant positive correlation between the expression of PGE2 and latent MMP-9 over the culture period. In addition, fetal membrane cultures directly stimulated with exogenous PGE2 secreted concentrations of latent MMP-9 comparable with those seen following FBS treatment by day 2, and the concentrations of PGE2 resulting in the significant elevation of latent MMP-9 (1–100 nmol/l) were comparable with the concentrations secreted by day 4 (1 nmol/l) following FBS stimulation.
Prostaglandin production fell after day 4 in culture, independent of a decrease in tissue viability, suggesting an overall reduction in the prostaglandin synthesis mechanism in our culture system. Arachidonic acid, which is derived from glycerophospholipids in cell membranes, is the rate-limiting step for the synthesis of prostaglandin. Given the minimal conditions used in the culture system, problems with the availability of this substrate may exist after 4 days and could explain the reduction in synthesis seen. Reductions in MMP-9 were also seen during this period, but whether this was due to the reduction in prostaglandin or a direct effect on the biosynthetic mechanism is unclear.
Prostaglandins can stimulate the production of MMPs in a number of systems, including blood monocytes (Corcoran et al., 1994) and ciliary smooth muscle cells (Lindsey et al., 1996; Weinreb et al., 1997). In these systems, both latent MMP-1 and MMP-3 were induced together with latent MMP-9, and the authors suggested a co-ordinated expression between these enzymes as a result of the common presence of the AP-1 regulatory element within their gene promoter regions. The co-ordinated expression of these MMPs with diverse extracellular matrix (ECM) substrate specificity would be an advantage in the breakdown of the complex ECM found in fetal membranes (Malak et al., 1993). Previous work has detected these MMPs in fetal membranes, throughout gestation and labour/delivery (Vadillo-Ortega et al., 1995; Bryant-Greenwood, 1998; Parry and Strauss, 1998), therefore such a co-ordination in expression may also be evident within our cultured fetal membranes. The possibility of other MMPs being induced by FBS stimulation within our culture system cannot be ignored, especially as latent MMP-9 shares common activation sites with a range of MMPs, including MMP-1 and MMP-3 (Borden and Heller, 1997).
The relationship between prostaglandin and latent MMP-9 production in fetal membranes was investigated by the use of the cyclo-oxygenase inhibitor, indomethacin. Incubation with indomethacin resulted in the almost total inhibition of PGE2 synthesis and a 70–80% reduction in the secretion of latent MMP-9. The latent MMP-9 concentrations obtained were below that seen in the absence of FBS, suggesting that the inhibitor could affect both constitutive as well as inducible components of the expression of latent MMP-9. This is consistent with indomethacin being a potent inhibitor of both the inducible COX-2, and the non-inducible COX-1, isoforms of the enzyme (Mitchell et al., 1993). Although this provides supporting evidence of the direct link between endogenous PGE2 production and the secretion of latent MMP-9, indomethacin is a non-specific prostaglandin inhibitor (Mitchell et al., 1993) and, therefore, we cannot rule out the possibility of a significant contribution by other prostaglandins.
The presence of prostaglandin within the fetal membranes will depend in part upon the balance between its synthesis and degradation. We have demonstrated the ability of our fetal membrane cultures to secrete prostaglandins which, in vivo, are synthesized predominately in the amnion (Sawdy et al., 1999). Fetal membranes also contain prostaglandin dehydrogenase which is responsible for its degradation. Regional differences in the expression of this enzyme (Van Meir et al., 1997) but not in prostaglandin synthesis (Sawdy et al., 1999), have been noted and it is suggested that in the region overlying the cervix the reduced activity of this enzyme in the cytotrophoblast cells could lead to an increase in the bioavaliability of prostaglandin within the fetal membranes. What is responsible for the generalized increases prostaglandin in vivo is unclear, although recent work using amnion WISH cell cultures (Hansen et al., 1998), implicates factors, e.g. tumour necrosis factor (TNF)
. TNF can simultaneously increase COX-2 activity, PGE2 concentration and the prostaglandin receptor EP1 in human amnion (Hansen et al., 1998). Interestingly, COX inhibition did not completely inhibit the secretion of MMP-9, 20–30% was unaffected. This suggests a significant prostaglandin-independent mechanism and/or a direct MMP stimulatory mechanism, which would be consistent with the observation that TNF is also a potent direct stimulator of MMP expression (Schwingshackl et al., 1999).
MMP-2 was also assessed in our culture system and, as with MMP-9, the predominant isoform identified was found to be latent. However, unlike MMP-9, its expression, as semi-quantified by gelatin zymography, did not respond to FBS, thus suggesting that latent MMP-2 is constitutively expressed in our culture system. Generally, MMP-2 is considered to be constitutively expressed and poorly regulated due to the lack of AP-1 and PEA-3 transactivator sequences within the promoter region and a unique TATA box (Yu et al., 1998).
Elevations in the concentrations of total-MMP-9 that occur in amniotic fluid have been implicated in the mechanisms of membrane rupture in term and preterm birth (Athayde et al., 1999; Locksmith et al., 1999). Studies by Vadillo-Ortega (1995) have demonstrated the presence of active and latent MMP-9 during labour and supports the role of active MMP-9 in fetal membrane rupture. The present study supports the contention that increases in prostaglandin prior to labour may mediate the local increase in latent MMP-9 concentrations. However, the mechanism underlying the labour-mediated activation of regional concentrations of MMP-9 needs to be addressed.
We propose that increases in prostaglandins (principally PGE2) may, in addition to their effects on uterine contractility and cervical `ripening', contribute to the eventual rupture of fetal membranes through their action on the expression of latent MMP-9. These data suggest that the expression and action of prostaglandins could be an important co-ordinating factor.
Acknowledgments
The authors would like to thank the theatre and administrative staff at Leicester Royal Maternity Hospital. This work was funded by The Tommy's Campaign and The University of Leicester, UK.
Notes
1 To whom correspondence should be addressed at: Preterm Birth Research Group, Department of Obstetrics and Gynaecology, University of Leicester, PO Box 65, Leicester LE2 7LX, UK. E-mail: jm50{at}leicester.ac.uk 
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Submitted on June 2, 2000; accepted on August 9, 2000.
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 W. Li and J. R. G. Challis Corticotropin-Releasing Hormone and Urocortin Induce Secretion of Matrix Metalloproteinase-9 (MMP-9) without Change in Tissue Inhibitors of MMP-1 by Cultured Cells from Human Placenta and Fetal Membranes J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6569 - 6574. [Abstract] [Full Text] [PDF]
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 S. Oger, C. Mehats, E. Dallot, D. Cabrol, and M.-J. Leroy Evidence for a Role of Phosphodiesterase 4 in Lipopolysaccharide-Stimulated Prostaglandin E2 Production and Matrix Metalloproteinase-9 Activity in Human Amniochorionic Membranes J. Immunol., June 15, 2005; 174(12): 8082 - 8089. [Abstract] [Full Text] [PDF]
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 S. Swarnakar, K. Ganguly, P. Kundu, A. Banerjee, P. Maity, and A. V. Sharma Curcumin Regulates Expression and Activity of Matrix Metalloproteinases 9 and 2 during Prevention and Healing of Indomethacin-induced Gastric Ulcer J. Biol. Chem., March 11, 2005; 280(10): 9409 - 9415. [Abstract] [Full Text] [PDF]
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 R. Menon and S. J. Fortunato The Role of Matrix Degrading Enzymes and Apoptosis in Repture of Membranes Reproductive Sciences, October 1, 2004; 11(7): 427 - 437. [Abstract] [PDF]
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W. Li, N. Alfaidy, and J. R. G. Challis Expression of Extracellular Matrix Metalloproteinase Inducer in Human Placenta and Fetal Membranes at Term Labor J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2897 - 2904. [Abstract] [Full Text] [PDF]
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 K Kashiwagi and S Tsukahara Effect of non-steroidal anti-inflammatory ophthalmic solution on intraocular pressure reduction by latanoprost Br. J. Ophthalmol., March 1, 2003; 87(3): 297 - 301. [Abstract] [Full Text] [PDF]
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 S. Ichihara, T. Senbonmatsu, E. Price Jr, T. Ichiki, F. A. Gaffney, and T. Inagami Targeted Deletion of Angiotensin II Type 2 Receptor Caused Cardiac Rupture After Acute Myocardial Infarction Circulation, October 22, 2002; 106(17): 2244 - 2249. [Abstract] [Full Text] [PDF]
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P. Xu, N. Alfaidy, and J. R. G. Challis Expression of Matrix Metalloproteinase (MMP)-2 and MMP-9 in Human Placenta and Fetal Membranes in Relation to Preterm and Term Labor J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1353 - 1361. [Abstract] [Full Text] [PDF]
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 U. Ulug, S. Goldman, I. Ben-Shlomo, and E. Shalev Matrix metalloproteinase (MMP)-2 and MMP-9 and their inhibitor, TIMP-1, in human term decidua and fetal membranes: the effect of prostaglandin F2{alpha} and indomethacin Mol. Hum. Reprod., December 1, 2001; 7(12): 1187 - 1193. [Abstract] [Full Text] [PDF]
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